4.3. Approaches to Peptidomimetic Design
4.3.3. Molecular Scaffolds Mimicking the Peptidic Backbone: Peptidomimetic Scaffolds
An important development in peptide/peptide secondary structure mimicry has been the emergence of molecules that are analogues of peptide secondary structures and mainly present in the main-chain polyamide backbone. These small molecules are the non-peptide peptidomimetics consisting of a central molecular entity containing suitable chemical appendages mimicking the pharmacophoric unit of original peptide bond responsible for biological activity. Thus, a peptidomimetic compound/molecule is thought of as a small molecule mimicking the biological activity of a peptide although being no longer a peptide in chemical nature.29 In generally, these molecules
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do not contain any peptide bonds and possess a modular structure deriving from amino acids, carbohydrates or other types of building blocks. The ideal peptidomimetic molecules are those which possess (a) favorable pharmacokinetics properties for oral administration, (b) improved proteolytic stability and specificity with respect to the parent bioactive peptide. Such constraint small structural entity/molecules constitute a “subset of bioisosteres” replacing a peptide bond(s) and called molecular “peptidomimetic scaffold”. The incorpotation of such scaffold in the peptide backbone allow the peptide to adopt a particular desired conformation of peptide secondary structure such as α-helix, β-sheet or β-turn.
Peptidomimetic scaffolds are basically developed according in two ways:(a) rational design approach based on structural information about the target or the biological activity of the parent peptide or conformational models of the parent peptide to ascertain the rationale for molecular recognition and (b) random screening method which relies on the random screening of wide arrays of small molecule mimetics of the parent bioactive peptide, followed by structural elaboration of hit compounds according to a rational approach based on available structural data. A combination of both approaches is the most successful route. A remarkable example of such a combined approach has been reported for the development of peptidomimetic ligands of the bradykinin receptor.30
In nature there are several secondary structures which are essential in protein function- α-helix, β- and γ-turn and, β-sheets. The goal of creating peptidomimetics of peptide secondary structures is a well-established approach in drug discovery aiming at fixing the bioactive conformations of a native peptide. This resulted in the development of peptidomimetic molecules of α-helix and β-sheet secondary structures, as well as in the design of a wide array of molecular scaffolds capable of replacing β- turns and loops, which are essential conformational components for peptides and proteins. Early examples of peptide secondary structure mimetics with designer scaffolds were reported by Hirschmann and Smith, who designed β-turn analogues based on sugar,31 steroid,32or even catechol33 backbones. Similarly, Hamilton34-56 and others37 used biphenyl,37a terphenyl,38, 39 and related40 scaffolds to mimic helices. Due to difficulties of protein folding in sheet structures, scaffolds that induce these β-sheet secondary structures are necessary in developing protein mimics.
Kemp and co-workers displayed in 1988 the first induced β-sheet mimic by utilizing hydrogen bonding and the rigidity of proline to artificially construct a β-sheet structure.
In the previous chapter (Chapter 3), a more detailed discussion was provided in respect of β-turn secondary structure. Herein, a sort and selective report of constraints molecular scaffolds is presented which demonstrate β-turn mimetics or act as β-turn inducing scaffolds.
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4.3.3.1. Molecular Scaffolds Mimicking/Inducing The β-Turns
As discussed, in the previous chapter, β-Turns are the most frequently mimicked protein secondary structures. It is the most prevalent turn motif found in proteins and is the four-residue β-turn, in which the i and i + 3 residues are hydrogen-bonded 41, 42–
43. The β-Turns are categorized based on the φ and ψ dihedral angles of the i + 1 and i + 2 amino acid residues, with the most common types being I, I′, II, and II′. An ideal mimic will have a rigid scaffold that can orient the side-chain residues in the same direction as the natural peptide thereby conferring better solubility and/or resistance to enzymatic degradation.
The generation of β-turn mimetics has been approached by two ways-(a) designing scaffolds that mimick the whole peptide motif (4.061) or (b) developing dipeptide isosteres capable of inducing a turn in a peptide motif (4.062). Furthermore, to stabilize β-turn structures, chemical tethers can be introduced as constraining elements within a (4.063) (Figure 4.5).
Figure 4.5. Approaches to β-turn mimetics.
The most popular approaches to reverse-turn peptidomimetics are based on the use of proline mimetics either at the i+1 or i+2 position to constrain a peptide conformation in a turn structure and to introduce δ-amino acids as dipeptide isosteres to replace the i+1−i+2 peptide moiety with a constrained scaffold.
4.3.3.1.1. Proline Analogues in 𝛃-Turn Peptidomimetics: Proline (4.064-4.065) and lactam-bridged molecular scaffolds (4.066) generated from proline by introducing suitable constraint elements, were reported as a powerful β-turn mimetics.44 Marshall et al. showed that the model peptides containing 2-azaproline (azPro) have a general tendency to prefer the type VI β-turn both in crystals and in organic solvents (4.067- 4.068) (Figure 4.6).45 A bicyclic α-amino acid scaffold, BGS, as turn inducers was reported which was incorporated at the i+1 position. The conformational study showed to adopt type II β-turn by the tetrapeptide containg BGS which was comparable to the conformation adopted by Val-d-Pro-Gly-Leu sequence as the reference peptide.46 The prevalence of the trans isomer at the Val–BGS amide bond in the model tetrapeptide demonstrated that a BGS compound can mimic exactly the
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trans-d-proline commonly found at the i+1 position of a type II β-turn. However, in a more competitive CD3CN solution it showed a preference for a more compact structure described by a γ-turn stabilized by 7- and 11-membered ring hydrogen- bonds, and in equilibrium with a β-hairpin-like structure (Figure 4.6).
Figure 4.6. β-Turns mimitics with proline/proline derived molecular scaffolds.
Many types of scaffolds have been employed, spanning from bi- and tricyclic molecules to spirolactam structures, which aim to nucleate a reverse-turn, to maintain the ten-membered ring intramolecular hydrogen-bond, and also to introduce additional constraints to the system.47, 48 Numerous mimics of β-turn substructures have been prepared over the past few decades, including those designed to act as folding nucleators.49 Examples ofother scaffolds include (a) δ-amino acid analogues in β-turn peptidomimetics, (b) biomolecular building blocks as scaffold for β-turn peptidomimetics some examples of all types are given below in Figure 4.7.
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Figure 4.7. Several β-turn mimetics.